We are in the midst of an epidemic of metabolic diseases such as obesity and diabetes, so a better understanding of the basic pathways of energy homeostasis is critical to the development of new medical therapies. Previous studies, including work funded under this grant, have shown that the PGC1 coactivators are major regulators of energy metabolism in mammalian systems. PGC1a regulates mitochondrial biogenesis and oxidative metabolism in many tissues, and links these genetic programs to the external environment. PGC1a controls important metabolic programs in the liver, brown fat, heart and skeletal muscle. In skeletal muscle, the PGC1a gene is induced during many kinds of exercise in mice and humans, and drives programs of mitochondrial biogenesis, fiber-type switching and resistance to atrophy/dystrophy. Most recently, we have shown that PGC1a initiates a novel program of angiogenesis that is potent and independent of the canonical HIF angiogenesis pathway. In preliminary data for this proposal, we show that the PGC1a gene gives rise to several novel proteins in muscle via alternative splicing. The original PGC1a (now called PGC1a1) and a new shorter form (termed PGC1a4) are both highly induced during exercise in mice. When expressed in primary culture or in vivo, PGC1a4 induced muscle cell hypertrophy but not mitochondrial biogenesis. This hypertrophy is associated with regulation of several genes of the myostatin and IGF1 pathways, both key signaling transduction systems of muscle growth. Our first Aim will test the hypothesis that PGC1a4 plays an important role in regulating physiological muscle hypertrophy and metabolic disease in vivo. To do this, we will create transgenic models of having both gain and loss of function of PGC1a4 in mice. We will combine these with different experimental models of muscle hypertrophy, atrophy and metabolic disease, including diet and age-induced obesity and diabetes. Our second Aim will investigate the mechanisms by which PGC1a4 can effect these changes in muscle cell growth and function. We will focus initially on the hypothesis that PGC1a4 works through the IGF1 and myostatin systems, since genes of these pathways are both robustly regulated by PGC1a4. Our last Aim will focus on the interaction between PGC1a1 and AMP kinase. We have created a murine strain with mutations in the AMPK sites in PGC1a1, and we will now critically test the hypothesis that this functional interaction contributes to the metabolic actions of both molecules in skeletal muscle and liver. Together, these studies promise to elucidate a major new pathway controlling skeletal muscle hypertrophy and muscle function. This has a direct impact on our ability to understand and provide new therapies in important diseases of aging, muscular dystrophies and obesity/diabetes.